MHC Class I genes are subject to both homeostatic, tissue-specific regulation and dynamic regulation. Among the mechanisms of dynamic regulation are those mediated by hormones that either increase or decrease transcription of the genes. The observation that thyroid stimulating hormone (TSH) leads to decreased class I transcription, whereas thyroid hormone increases it, led to the hypothesis that failure to appropriately regulate MHC class I molecules may play a pivotal role in the generation of autoimmune disease. Consistent with this hypothesis, we have shown that in experimental models of autoimmune systemic lupus erythematosus and blepharitis, animals that fail to express class I are resistant to disease. In contrast, class I- animals are susceptible to EAE. To further characterize the role of class I expression in autoimmune disease, we have studied the effect on induction of disease of a pharmacological agent, MMI, that reduces class I expression. Treatment of mice with experimental SLE or blepharitis reduces the incidence and severity of disease. In addition, MMI-treatment of NZBXNZW mice, which develop a spontaneous systemic autoimmune disease, also significantly reduces the severity and incidence of immune complex deposits in their kidneys. Studies are in progress to determine the molecular mechanisms by which reduction of class I expression abrogates the development of certain classes of autoimmune disease.